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Chapter 3. Antigens Terminology: Hapten - a Small Molecule That Is Antigenic but Not (By Itself) Immunogenic

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Chapter 3. Antigens Terminology: Hapten - a Small Molecule That Is Antigenic but Not (By Itself) Immunogenic Chapter 3. Antigens Terminology: Hapten - a small molecule that is antigenic but not (by itself) immunogenic. Antigen : Substances that can be recognized by the surface antibody (B cells) or by the TCR when associated with MHC molecules Antibodies can be made to haptens only after the Immunogenicity VS Antigenicity: hapten is covalently conjugated to a large protein Immunogenicity – ability to induce an antibody and/or “carrier”. cell-mediated immune response Antigenicity – ability to combine with the final products of the response (antibodies and/or T cell receptor) NOTE: Most immunogenic molecules are also antigenic Figure 5.1 1 Factors that influence immunogenicity: - Foreign-ness – non-self (far apart evolutionary) 2 - Type of molecule (chemical nature) - protein > polysaccharide > lipid > nucleic acid - Size - larger molecules tend to be more immunogenic 3 -Composition - heterogeneity increases immunogenicity. - 4ry > 3ry > 2ry > 1ry structure -Degradability - protein antigens must be degraded (phagocytosis) in order to be presented to helper T cells . - Physical Form - Denatured > Native Additional factors that influence the immune response: - Genetics of the recipient (genotype - MHC) - Dosage of the antigen (optimal dose - tolerance) - Number of doses of the antigen (boosters) - Route of administration of the antigen - intravenous (spleen) - subcutaneous (lymph nodes) - intraperitoneal (lymph nodes) - oral (mucosal) - inhaled (mucosal) - Use of adjuvant 1 Commonly used adjuvants: (Table 3.3) Adjuvant : a substance that, when mixed with an antigen Alum - aluminum potassium sulfate - precipitates the antigen, and injected with it, serves to enhance the immune resulting in increased persistence of the antigen. Mild response to the antigen. granuloma. Possible mechanisms of action of adjuvants : Incomplete Freund’s adjuvant - mineral oil-based - increases - Prolong the persistence of the antigen , thus giving the persistence of the antigen, mild granuloma, and induces co- immune system more time to respond stimulatory signals. - Increase the “size” of the antigen by causing aggregation , Complete Freund’s Adjuvant - mineral oil-based adjuvant containing dead Mycobacterium - increases persistence of - Stimulate lymphocyte proliferation and/or activation the antigen, stimulates a chronic inflammatory response - Stimulate a local inflammatory response , thus recruiting (granuloma ), and co-stimulatory signals. Activates cells to the site of the antigen (GRANULOMA) Macrophages and DCs. - Enhance co-stimulatory signals Bacterial Lipopolysaccharides - stimulate nonspecific lymphocyte activation and proliferation, and co- stimulatory signals. Epitope or Antigenic Determinant - the region INCREASED COMPLEXITY of an antigen that binds to a T cell receptor or a B cell receptor (antibody). - Since an epitope is the part of the antigen that binds to the B cell or T cell antigen receptor, it is the part that determines the antigenicity of the antigen - thus the term “antigenic determinant ”. -T and B cells recognize different epitopes on an - Each different protein and glycoprotein of a virus (or bacterium antigen or foreign cell) constitutes a different antigen - Each different antigen contains a number of different epitopes Properties of B cell epitopes (Table 3-4) Denaturation!!!! - Usually dependent on the native, tertiary conformation of the antigen (PROTEIN FOLDING) PROTEIN - Must be accessible - tend to be on the “surface” of the FOLDING antigen (hydrophilic) - May be made of sequential or non-sequential amino acid sequences (epitopes made up of non-sequential amino acid sequences are called “conformational epitopes”). - Binds to soluble antigen, No MHC molecule requirement - Large antigens contain multiple, overlapping B cell epitopes. 2 Properties of B cell epitopes (Table 3-4) HYDROPHILIC - Usually dependent on the native, tertiary conformation of the antigen - Must be accessible - tend to be on the “surface” of the antigen (hydrophilic) - May be made of sequential or non-sequential amino acid sequences (epitopes made up of non-sequential amino acid sequences are called “conformational epitopes”). - Binds to soluble antigen, No MHC molecule requirement - Large antigens contain multiple, overlapping B cell epitopes. Properties of B cell epitopes (Table 3-4) - Usually dependent on the native, tertiary conformation of the antigen - Must be accessible - tend to be on the “surface” of the Anti-lysozyme (-) antigen (hydrophilic) Anti-lysozyme (+) - May be made of sequential or non-sequential amino acid sequences (epitopes made up of non-sequential amino acid sequences are called “conformational epitopes ”). Anti-lysozyme (+) - Binds to soluble antigen, No MHC molecule requirement - Large antigens contain multiple, overlapping B cell epitopes. Properties of B cell epitopes (Table 3-4) - Usually dependent on the native, tertiary conformation of the antigen - Must be accessible - tend to be on the “surface” of the antigen (hydrophilic) - May be made of sequential or non-sequential amino acid A sequences (epitopes made up of non-sequential amino acid sequences are called “conformational epitopes”). B ** - Binds to soluble antigen, No MHC molecule requirement 1. Antibody binding may be lost after a protein is denatured!! - Large antigens contain multiple, overlapping B cell 2. ??? epitopes. 3 Properties of B cell epitopes (Table 3-4) - Usually dependent on the native, tertiary conformation of the antigen - Must be accessible - tend to be on the “surface” of the antigen (hydrophilic) - May be made of sequential or non-sequential amino acid sequences (epitopes made up of non-sequential amino acid sequences are called “conformational epitopes”). "B-lymphocytes have sIg molecules on their surface that recognize - Binds to soluble antigen, No MHC molecule epitopes directly on antigens. Different B-lymphocytes are requirement programmed to produce different molecules of sIg, each specific for a unique epitope." - Large antigens contain multiple, overlapping B cell epitopes. animation and pictures from http://www.cat.cc.md.us/courses/bio141/lecguide/unit3/epsig.html Large antigens contain multiple, Properties of T cell epitopes (Table 3-4) overlapping B cell epitopes. - Involves a tertiary complex: T cell receptor, antigen, and MHC molecule Amino acids 1-12 Epitope 1 - Must be accessible - tend to be on the “surface” of the Amino acids 8-20 Epitope 2 antigen (hydrophilic) Amino acids 19-33 Epitope 3 - May be made of sequential or non-sequential amino acid sequences (epitopes made up of non-sequential amino acid sequences are called “conformational 1 10 20 30 110 epitopes”). Linear or Sequential Antigen - Binds to soluble antigen, No MHC molecule requirement Would this cause cross-reactivity? - Large antigens contain multiple, overlapping B cell epitopes. Properties of T cell epitopes (Table 3-4) - Involves a tertiary complex: T cell receptor, antigen, and MHC molecule 3 - Internal linear peptides ( hydrophobic ) produced by 4 processing and bound to MHC molecules 2 - Binds to soluble antigen, No MHC molecule requirement 1 - Large antigens contain multiple, overlapping B cell epitopes. 4 Properties of T cell epitopes (Table 3-4) - Involves a tertiary complex: T cell receptor, antigen, and MHC molecule - Internal linear peptides (hydrophobic) produced by processing and bound to MHC molecules - Does not bind to soluble antigen, APC processing - Recognize mostly proteins but some lipids and glycolipids can be presented on MHC-like molecules Properties of T cell epitopes (Table 3-4) - Involves a tertiary complex: T cell receptor, antigen, and MHC molecule - Internal linear peptides (hydrophobic) produced by processing and bound to MHC molecules - Does not bind to soluble antigen, APC processing - Recognize mostly proteins but some lipids and glycolipids can be presented on MHC-like molecules (remember CD1 molecules!) Must be processed & presented with MHC in APC!!!! Immunoglobulin Structure and Function 5 1 - Each heavy and light chain 2 is made up of a number of domains (= Ig folding or Ig domains ). * * - Light chains consist of 2 domains ( C and V ). - Heavy chains have 4-5 domains (depending on * the class of antibody) - Each domain is about 110 Heavy chain= 446 aa Light chain= 214aa amino acids in length and 1 2 contains an intrachain disulfide bond between Constant Regions two cysteines about 60 amino acids apart. Variable Regions -150,000 molecular weight Basic Antibody Structure • Multiple myeloma = cancerous plasma cells • Monomer = 150,000 1 2 3 4 What is the difference? - Constant (C) and Variable (V) regions RECAP: - The Fc region plays NO role in antigen binding. 100,000 MW 3 (Fab) 2 - Papain breaks antigen molecules into 2 Fab fragments and an Fc fragment. - Pepsin breaks antibody molecules into an F(ab’)2 fragment and a VERY SMALL pFc’ fragment. 1 2 - Mercaptoethanol treatment results in 2 heavy and 2 2 (50,0000) light chains 2 (25,000) 2 H + 2 L - Complexes of antibodies cross-linked by antigen are Papain 1 called “immune complexes”. 2 (45,000) 1 (50,000) 2 Fab + Fc 6 1. Constant region - amino Summary acid sequence in the C- terminal regions of the H and • Molecule consists of Constant and Variable regions for 1 L chains is the same . both Light and Heavy chains (C H, V H, C L, V L) 2 • Ig molecule made of domains 2. Variable region - amino 1 • Domains ~ 110 aa 3 acid sequence in the N- terminal regions of the H and • Each antigen-binding site is made up of the N-terminal L chains is different . This domain of the heavy and
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